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Background: The induced repolarization of tumor growth-promoting M2 macrophages into tumor growth-inhibiting M1 macrophages is a matter of intensive research and is expected to lead towards a novel targetable approach in HCC therapy. Methods: Differentially expressed M2 macrophage-related genes between normal and tumor samples with high and low M2 macrophage infiltration in the Gene Expression Omnibus (GEO) and TCGA datasets were identified. A risk score was constructed based on univariate Cox analysis and LASSO-penalized Cox regression analysis. The relationship between the different risk score groups and clinical pathological characteristics as well as immune infiltration characteristics was studied. Subsequently, a nomogram was constructed to predict patients' prognosis. Western blot and RT-qPCR were carried out to validate the results in human HCC samples. Results: Increased M2 macrophage infiltration was associated with a shorter overall survival (OS). Four important M2 macrophage-related genes (SLC22A1, CPS1, SLC10A1, CYP2C9) were discovered to be strongly correlated with OS and M2 macrophage infiltration. A nomogram incorporating the signature and tumor stage was developed for final clinical translation. Conclusions: SLC22A1, CPS1, SLC10A1 and CYP2C9 genes are associated with tumor-promoting M2 macrophage infiltration and might be potential targets for macrophage-related immunotherapy in HCC patients. Further, this four-gene signature is a potential tool for predicting prognosis in these patients. [ABSTRACT FROM AUTHOR]

Background Proenkephalin A 119–159 (penKid) is a novel blood biomarker for real-time assessment of kidney function and was found to be independently associated with worsening kidney function and mortality. A novel penKid-based estimated glomerular filtration rate equation (eGFRPENK-Crea), outperforms current creatinine-based eGFR equations in predicting iohexol or iothalamate plasma clearance-based measured GFR. In this study, we aimed to evaluate the predictive value of penKid and eGFRPENK-Crea for all-cause mortality in stable patients at high cardiovascular risk. Methods Circulating penKid levels were assessed in 615 stable patients hospitalized at the Department of Cardiology at University Hospital Aachen, Germany. The endpoint was all-cause mortality; follow up was 3 years. Results penKid levels were higher in 46 non-survivors [58.8 (IQR 47.5–85.0) pmol/l] compared to 569 survivors [43.8 (IQR 34.0–58.0) pmol/l; P  < .0001]. Univariable Cox regression analyses found penKid and eGFRPENK-Crea to be associated with all-cause mortality (C index 0.703, χ 2 33.27, P  < .00001; C index 0.716, χ 2 36.51, P  < .00001). This association remained significant after adjustment for significant baseline parameters including age, smoking, chronic heart failure, use of diuretics, leucocytes, body mass index, sex, and creatinine (C index 0.799, χ 2 72.06, P  < .00001). Importantly, penKid provided significant added value on top of eGFRCKD-EPI 2021 (eGFRCKD-EPI 2021: C index 0.716, χ 2 34.21; eGFRCKD-EPI 2021 + penKid: C index 0.727, χ 2: 40.02; Delta χ 2 5.81; all P  < .00001) for all-cause mortality prediction in our cohort. Conclusions penKid levels and eGFRPENK-Crea is associated with all-cause mortality within a 3-year follow-up period and the addition of penKid on top of eGFRCKD-EPI 2021 provided significant added value in mortality prediction. [ABSTRACT FROM AUTHOR]

The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients. [ABSTRACT FROM AUTHOR]

Intrahepatic cholangiocarcinoma is a common primary liver tumor with limited treatment options and poor prognosis. Changes in body composition (BC) have been shown to affect the prognosis of various types of tumors. Therefore, our study aimed to investigate the correlation between BC and clinical and oncological outcomes in patients with iCCA. All patients with iCCA who had surgery from 2010 to 2022 at our institution were included. We used CT scans and 3D Slicer software to assess BC and conducted logistic regressions as well as Cox regressions and Kaplan–Meier analyses to investigate associations between BC and clinical variables with focus on postoperative complications and oncological outcomes. BC was frequently altered in iCCA (n = 162), with 53.1% of the patients showing obesity, 63.2% sarcopenia, 52.8% myosteatosis, 10.1% visceral obesity, and 15.3% sarcopenic obesity. The multivariate analysis showed no meaningful association between BC and perioperative complications. Myosteatosis was associated with reduced overall survival (OS) in iCCA patients (myosteatosis vs. non-myosteatosis, 7 vs. 18 months, p = 0.016 log rank). Further, the subgroup analysis revealed a notable effect in the subset of R0-resected patients (myosteatosis vs. non-myosteatosis, 18 vs. 32 months, p = 0.025) and patients with nodal metastases (myosteatosis vs. non-myosteatosis, 7 vs. 18 months, p = 0.016). While altered BC is not associated with perioperative outcomes in iCCA, myosteatosis emerges as a prognostic factor for reduced OS in the overall and sub-populations of resected patients. [ABSTRACT FROM AUTHOR]